Chiral, non-racemic alkylated derivatives, including but not limited to chiral hydroxy-alkyl derivatives, of nitrogen-containing heterocycles such as pyrrolidine, are desirable for preparing a variety of compounds, including pharmaceutically active compounds. Chiral hydroxy-alkyl derivatives of nitrogen-contining heterocycles are typically needed in large quantities and good enantiomeric excess (ee) in drug discovery efforts. These derivatives are useful precursors in the synthesis of compounds such as Anthramycin, Lydicamycin, Halosaline, and Cuscohygrine, and also in the synthesis of many bioactive molecules, such as clemastine (antihistamine), (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol (a 5-HT7 receptor modulator), and SB-269970 (5HT7 receptor antagonist). See, for example, O'Neil, I. A., Murray, C. L., Potter, A. J., Kalindjian, S. B., Tetrahedron Lett. 1997, 38, 3609-3610; Hayakawa, Y., Kanamaru, N., Morisaki, N., Seto, H., Furihata, K., Tetrahedron Lett. 1991, 3, 213-216; Takahata, H., Kubota, M., Ikota, N., J. Org. Chem. 1999, 64, 8594-8601; Stapper, C., Blechert, S., J. Org. Chem. 2002, 67, 6456-6460; Manthorpe, J. M., Gleason, J. L., J. Am. Chem. Soc. 2001, 123, 2091-2092; Danilewicz, J. C., Abel, S. M., Brown, A. D., Fish, P. V., Hawkeswook, E., Holland, S. J., James, K., McElroy, A. B., Overington, J., Powling, M. J., Rance, D. J., J. Med. Chem. 2002, 45, 2432-2453; Stanchev, S., Rakovska, R., Berova, N., Snatzke, G., Tetrahedron: Asymmetry 1995, 6, 183-198; Lovell, P. J., Bromidge, S. M., Dabbs, S., Duckworth, D. M., Forbes, I. T., Jennings, A. J., King, F. D., Middlemiss, D. N., Rahman, S. K., Saunders, D. V., Collin, L. L., Hagan, J. J., Riley, G. J., Thomas, D. R., J. Med. Chem. 2000, 43, 342-345; Cardillo, G., Gentilucci, L., Qasem, A. R., Sgarzi, F., Spampinato, S., J. Med. Chem. 2002, 45, 2571-2578; Vernier, J-M, El-Abdellaoui, H., Holsenback, H., Cosford, N. D. P., Bleicher, L., Barker, G., Bontempi, B., Chavez-Noriega, L., Menzaghi, F., Rao, T. S., Reid, R., Sacaan, A. I., Suto, C., Washburn, M., Lloyd, G. K., McDonald, I. A., J. Med. Chem. 1999, 42, 1684-1686; DeVita, R. J., Goulet, M. T., Wyvratt, M. J., Fisher, M. H., Lo, J-L, Yang, Y. T., Cheng, K., Smith, R. G., Bioorg. Med. Chem. Lett. 1999, 9, 2621-2624. One example of such chiral hydroxy-alkyl derivatives of N-containing heterocycles is (2R)-2-(2-hydroxy-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, also known as (+)-(2R)-1-Boc-2-(2-hydroxy-ethyl)-pyrrolidine, a compound of formula (Ia), or its deprotected form, a compound of formula (Ia′):

Conventional methods to synthesize chiral hydroxy-alkyl derivatives of nitrogen-containing heterocycles, such as a compound of formula (Ia), involve multiple step sequences from starting materials that are themselves chiral, and often expensive, such as D-prolinol or D-proline. Suitable chiral starting materials having nitrogen-containing heterocycles with rings smaller or larger than five members are often not commercially available. These starting materials, however, are not regarded as being suitable for large-scale synthesis. See, for example, O'Neil, I. A.; Murray, C. L.; Potter, A. J., Kalindjian, S. B., Tetrahedron Lett. 1997, 38, 3609-3610; Lovell, P. J.; Bromidge, S. M., Dabbs, S., Duckworth, D. M.; Forbes, I. T.; Jennings, A. J.; King, F. D.; Middlemiss, D. N.; Rahman, S. K.; Saunders, D. V.; Collin, L. L.; Hagan, J. J., Riley, G. J., Thomas, D. R., J. Med. Chem. 2000, 43, 342-345; Cardillo, G., Gentilucci, L., Qasem, A. R., Sgarzi, F., Spampinato, S., J. Med. Chem. 2002, 45, 2571-2578; Vernier, J-M, El-Abdellaoui, H., Holsenback, H., Cosford, N. D. P., Bleicher, L., Barker, G., Bontempi, B., Chavez-Noriega, L., Menzaghi, F., Rao, T. S., Reid, R., Sacaan, A. I., Suto, C., Washburn, M., Lloyd, G. K., McDonald, I. A., J. Med. Chem. 1999, 42,1684-1686; and DeVita, R. J., Goulet, M. T., Wyvratt, M. J., Fisher, M. H., Lo, J-L, Yang, Y. T., Cheng, K., Smith, R. G., Bioorg. Med. Chem. Lett. 1999, 9, 2621-2624.
Scheme 1a provides an example of such conventional synthetic methodology that starts with a chiral compound and relies on four steps to generate compound (Ia).

With respect to Scheme 1a, a compound of formula (Ia) is prepared from a chiral starting material (D-prolinol). The reference letters a-d depicted with the reaction steps in the same scheme are given with the following meanings: (a) BOC2O, THF/H2O, K2CO3; (b) CH3SO2Cl, Et3N, CH2Cl2; (c) NaCN, DMF; and (d) hydrolysis to a methyl ester and then reduction in the presence of LiAlH4, Et2O, as in the last step of Scheme 1b.
Scheme 1b provides another example of conventional synthetic methodology that starts with a chiral compound and relies on a plurality of steps to generate compound (Ia).

With respect to Scheme 1b, a compound of formula (Ia) is prepared from a chiral starting material (D-proline) according to the synthetic steps shown therein.
Figures given as percentages in reaction steps refer to yields in the respective steps. For example, the figure “95%” in Scheme 1b means that the last step in such Scheme produces the final product with a yield of 95% (which unless indicated otherwise is calculated in terms of mass with respect to the maximum theoretically possible quantity of product that could be obtained in that step).
It is desirable to prepare chiral alkylated derivatives of nitrogen-containing heterocycles, such as compound of formula (Ia), from readily available inexpensive starting materials. Low complexity starting materials, such as achiral compounds are typically desirable, for they are generally more readily available and/or less expensive than chiral counterparts. It is also desirable that the, synthetic methods be suitable for large-scale synthesis, and that they involve a small number of steps, preferably one step. Where chirality is involved, it is also desirable to develop a synthesis that is as highly stereoselective as possible, so that a high ee of the product reduces, or even eliminates, the need for subsequent isolation and purifiction steps. In addition, desirable synthetic methods should preferably generate the chiral alkylated derivatives of nitrogen-containing heterocycles, such as compound of formula (Ia), in high yield.
Embodiments of the present invention provide desirable features such as those refered to above. Furthermore, embodiments of this invention provide synthetic methods for chiral alkylated derivatives of nitrogen-containing heterocycles, such as chiral hydroxy-alkyl derivatives of nitrogen-containing heterocycles, including a compound of formula (Ia), that solve synthetic problems that are not known to have been solved, or even addressed, by conventional methodologies.
For example, (−)-sparteine-mediated asymmetric deprotonative lithiation has been used to generate chiral carbanions. See, for example, Hoppe, D., Hense, T., Angew. Chem. Int. Ed. Engl. 1997, 36, 2282-2316; Beak, P., Basu, A., Gallagher, D. J., Park, Y. S., Thayumanavan, S., Acc. Chem. Res. 1996, 29, 552-560; Johnson, T. A., Jang, D. O., Slafer, B. W., Curtis, M. D., Beak, P., J. Am. Chem. Soc. 2002, 124,11689-11698; Laumer, J. M., Kim, D. D., Beak, P., J. Org. Chem. 2002, 67, 6797-6804; Lim, S. H., Beak, P., Org. Lett. 2002, 4, 2657-2660; Johnson, T. A., Curtis, M. D., Beak, P., Org. Lett. 2002, 4, 2747-2749; Christoph, G., Hoppe, D., Org. Lett. 2002, 4, 2189-2192; Arrasate, S., Lete, E., Sotomayor, N., Tetrahedron: Asymmetry 2002, 13, 311-316; and Metallinos, C., Snieckus, V., Org. Lett. 2002, 4, 1935-1938. Furthermore, a reportedly readily available (+)-sparteine surrogate has been introduced for its use in place of (+)-sparteine, which is not commercially available. See, for example, Dearden, M. J., Firkin, C. R., Hermet, J. R., O'Brien, P., J. Am. Chem. Soc. 2002, 124,11870-11871.
Conventional methods, however, rely on strong electrophiles, such as TMSCl, Bu3SnCl, Me2SO4, aldehydes, and ketones. See, for example, Beak, P., Kerrick, S. T., Wu, S. D., Chu, J. X., J. Am. Chem. Soc. 1994, 116, 3231-3239. In contrast, methodology according to this invention uses weak electrophiles, such as strained cyclic ethers. Conventional methodology does not address the suitability of weak electrophiles. In addition, conventional methodology does not address the conditions under which such electrophiles could be used effectively. Even more specifically, conventional methodology does not address the issue of whether weak electrophiles could be used at all. Furthermore, conventional methodology does not appear to suggest the results of using such eletrophiles, even if such use could be effectively implemented. Moreover, the reported use (see, for example, Dearden, M. J., Firkin, C. R., Hermet, J. R., O'Brien, P., J. Am. Chem. Soc. 2002, 124, 11870-11871) of an epoxide in an intramolecular example wherein the epoxide opening is not activated by complexation with a Lewis acid, does not teach the use, in the presence of a Lewis acid, of a strained cyclic ether in an intermolecular process as an electrophilic partner of a sparteine/organometallic complex. Although Lewis acids have been reported as being capable of activating an epoxide for nucleophilic attack, and alkyl lithium reagents have been reported to react with epoxides that have been activated with BF3.Et2O (see, for example, Yamaguchi, N., Hirao, I., Tetrahedron Lett. 1983, 24, 391-394; Bachi, M. D., Bosch, E., Tetrahedron Lett. 1986, 27, 641-644), such reported activations do not address the chiral synthesis with sparteine-organometallic complexes and Lewis acid-activated strained cyclic ethers from achiral nitrogen-containing heterocycles.
In contrast with the conventional methodologies, embodiments of this invention provide efficient one-step methods for synthesizing versatile precursors of many bioactive molecules in high efficiency and enantioselectrivity by nucleophilic ring opening of a strained cyclic ether by a chiral N-heterocycle-metal-diamine complex, promoted by a Lewis acid.
References cited throughout the specification are incorporated herein by reference.